The long-term objective of this proposal is to improve the therapeutic approach for patients with acute promyelocytic leukemia (APL) by clarifying the pathogenesis of the life-threatening bleeding disorder associated with this disease. We will correlate the profibrinolytic, procoagulant and/or proinflammatory properties of APL cells (from patients) with the development of disseminated intravascular coagulation (DIC) and/or hyperfibrinolysis before, during and following induction chemotherapy or treatment with all-trans retinoic acid (ATRA). We will test the hypothesis that the synthesis of these mediators by APL cells can be suppressed by ATRA, thus accounting for the rapid reversal of the coagulopathy in patients with APL treated with this "differentiation" inducing approach (in contradistinction the typical exacerbation of the coagulopathy in patients treated with conventional chemotherapy). Utilizing specific probes for urokinase plasminogen activator (u-PA), tissue PA (t-PA), u-PA receptors, PA inhibitors 1 and 2 (PAI-1/PAI-2), tissue factor (TF), cancer procoagulant (CP) and interleukin-1 (IL-1), we will quantify the expression of these profibrinolytic and procoagulant/proinflammatory proteins in APL cells and correlate the levels with the presence/absence of DIC/hyperfibrinolysis in patients. Plasma samples will be assayed using routine tests for DIC and hyperfibrinolysis and by measuring levels of plasminogen, d-Dimer, t-PA, u-PA, plasmin, fibrinopeptide A (FPA), prothrombin fragment F1.2 (Pro F1.2), thrombin-antithrombin (TAT) complexes and IL-1 beta. Bone marrow and plasma samples will be obtained from patients entered on a large international phase III intergroup trial, which randomizes patients with newly-diagnosed APL to receive either ATRA or conventional chemotherapy. 1. To characterize the pathogenesis of the coagulopathy in APL in a prospective clinical trial. a. We will test the primary hypothesis that disordered regulation of fibrinolysis is associated with the bleeding diathesis in patients with APL by correlating plasma and cellular markers of activation of fibrinolysis with the occurrence of hemorrhagic toxicity de novo in patients on EST 2491. b. We will test the secondary hypothesis that in some patients with APL, the elaboration of tumor cell procoagulants and/or proinflammatory mediators is associated with the occurrence of hemorrhagic toxicity. We will correlate the levels of expression of these mediators with the levels of the plasma markers for the activation of clotting and with the presence/absence of DIC in patients on EST 2491 (de novo). 2. To test the hypothesis that ATRA rapidly ameliorates the bleeding diathesis in patients with APL by downregulating the synthesis of profibrinolytic, procoagulant and/or proinflammatory mediators by APL cells. 3. To establish a repository of APL cellular mRNA, cell extracts, fixed cell preparations and anticoagulated plasma samples for future studies.